Biomedical subjects

D Chen

Publications and source records attributed to D Chen.

927 records · Page 52Linked to original sources

PubMedDate not supplied

Physiology of the ECL cells.

The enterochromaffin-like (ECL) cells of the oxyntic mucosa (fundus) of the stomach produce, store and secrete histamine, chromogranin A-derived peptides such as pancreastatin, and an unanticipated but as yet unidentified peptide hormone. The cells are stimulated by gastrin and pituitary adenylate cyclase activating peptide and suppressed by somatostatin and galanin. Choline esters and histamine seem to be without effect on ECL cell secretion. The existence of a gastrin-ECL cell axis not only explains how gastrin stimulates acid secretion but also may help to explore the functional significance of the ECL cells with respect to the nature and bioactivity of its peptide hormone. From the results of studies of gastrectomized/fundectomized and gastrin-treated rats, it has been speculated that the anticipated ECL-cell peptide hormone acts on bone metabolism.

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PubMedDate not supplied

Physiological significance of ECL-cell histamine.

In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin injection or pylorus ligation) was unaffected by alpha-FMH treatment but inhibited by an H2 antagonist. These results suggest that gastrin stimulates acid secretion via release of ECL-cell histamine, whereas vagally-induced acid secretion--although histamine-dependent--does not rely on ECL-cell histamine. Gastrin is known to have a trophic effect on the oxyntic mucosa. By combining long-term hypergastrinemia with continuous infusion of alpha-FMH, we were able to show that gastrin-evoked trophic effects in the stomach do not depend on ECL-cell histamine.

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PubMedDate not supplied

ECL cell morphology.

Using immunohistochemistry at the conventional light, confocal and electron microscopic levels, we have demonstrated that rat stomach ECL cells store histamine and pancreastatin in granules and secretory vesicles, while histidine decarboxylase occurs in the cytosol. Furthermore the ECL cells display immunoreactivity for vesicular monoamine transporter type 2 (VMAT-2), synaptophysin, synaptotagmin III, vesicle-associated membrane protein-2, cysteine string protein, synaptosomal-associated protein of 25 kDa, syntaxin and Munc-18. Using electron microscopy in combination with stereological methods, we have evidence to suggest the existence of both an exocytotic and a crinophagic pathway in the ECL cells. The process of exocytosis in the ECL cells seems to involve a class of proteins that promote or participate in the fusion between the granule/vesicle membrane and the plasma membrane. The granules take up histamine by VMAT-2 from the cytosol during transport from the Golgi zone to the more peripheral parts of the cells. As a result, they turn into secretory vesicles. As a consequence of stimulation (e.g., by gastrin), the secretory vesicles fuse with the cell membrane to release their contents by exocytosis. The crinophagic pathway was studied in hypergastrinemic rats. In the ECL cells of such animals, the secretory vesicles were found to fuse not only with the cell membrane but also with each other to form vacuoles. Subsequent lysosomal degradation of the vacuoles and their contents resulted in the development of lipofuscin bodies.

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PubMedDate not supplied

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

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PubMedDate not supplied

The biology and pathobiology of the ECL cells.

The enterochromaffin-like (ECL) cells represent the predominant endocrine cell population in the acid-producing part of the stomach of both experimental animals and man. These cells actively produce and store histamine in addition to an anticipated but as yet unidentified peptide hormone and are under the control of gastrin. An acute gastrin stimulus causes exocytosis of the cytoplasmic granules/vesicles (and release of histamine and activation of the histamine-forming enzyme, histidine decarboxylase), while a more sustained gastrin stimulus causes first hypertrophy and then hyperplasia of the ECL cells in the rat (at most, a fivefold increase in the cell number). These effects can be demonstrated following infusion of gastrin or following an increase in the concentration of circulating gastrin of endogenous origin. The growth of the ECL cells reflects an accelerated self-replication rate. As studied in the rat, the self-replication rate is accelerated quite soon after induction of hypergastrinemia (blockade of acid secretion), the rate is maximally elevated within two weeks and then declines to control values at ten and 20 weeks despite the sustained hypergastrinemia. Lifelong hypergastrinemia in rats is associated not only with ECL-cell hyperplasia but also with an increased incidence of ECL-cell carcinoids. Recently, we could show that alpha-fluoromethylhistidine, which is a suicide inhibitor of histidine decarboxylase, effectively depletes the ECL cells of histamine and that the histamine-depleted ECL cells respond to gastrin with hyperplasia in a manner identical to normal ECL cells. Other factors beside gastrin seem to participate in the control of ECL-cell function and proliferation. Although exogenous somatostatin is known to suppress the activity of the ECL cells, we have failed to obtain evidence that the somatostatin cells in the oxyntic mucosa play a role in the physiological control of the ECL cells. The vagus, however, is important for the ability of the ECL cells to respond to gastrin. This conclusion is based on the observation that vagal denervation suppresses the hyperplastic response of the ECL cells to gastrin. Porta-cava shunting, on the other hand, greatly enhances the responsiveness of the ECL cells to gastrin. The mechanism behind this effect is unknown.

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PubMedDate not supplied

[Prognosis of severe trauma outcome using noninvasive monitoring].

The purpose of the case study was, firstly, to evaluate (starting from the time the patients are admitted to the intensive care unit--ICU) a type of cardiac, pulmonary and peripheral microcirculation in patients with severe traumas by using a multi-component and invasion-free monitoring; the second purpose was to measure quantitatively the changes in the cardiac, pulmonary and peripheral hemodynamics leading to recovery or death; and finally, it was to investigate the effectiveness of applying the discriminative analysis for the sake of assessing the biological value of the controllable changes and of forecast outcome. The invasion-free monitoring system comprising the below tools was in use: an improved bio-impedance method (evaluation of the cardiac output), pulsometry (examination of the pulmonary function), transcutaneous oxygen pressure (tissue perfusion function) and arterial blood pressure (ABP--general circulation status). The results of continuously controllable invasion-free measurements were used for a prospective evaluation at the emergency unit of the county hospital, which was supervised by the university. The accumulated integral values of the deficit or excess of each controllable parameter were calculated by using the differences between the normal values and the values obtained for each patient and for the groups of survivors and dead. A probable outcome and a degree of the deficit of the pulmonary and cardiac functions as well as of the tissue-perfusion function were analyzed by using the discriminant function. The values of pure aggregate deficits (-) or excesses (+) were for the survivors and dead, respectively, as follows: cardiac index--(+)93 +/- 49.8 l/m2 versus -232 +/- 138 l/m2 (p < 0.07); mean ABD(-)-12 +/- 12.4 mm Hg versus -57 +/- 23.5 mm Hg (p < 0.066); arterial saturation(-)-1 +/- 0.09% h versus -9 +/- 2.6% h (p < 0.001): and tissue perfusion--(+)311 +/- 87 tor/h versus 793 +/- 175 tor/h (p < 0.0001). The pure aggregate value of reduced circulation, tissue perfusion and of hypoxemia degree was found to be higher in the dead versus the survivors. The invasion-free monitoring systems secure a constant real-time control over the data, which makes the circulatory malfunction revealed as soon as possible in emergency settings. The mentioned systems can be used to describe, for each patients, a temporal hemodynamic model and to evaluate quantitatively a functional-deficit severity; they also provide for composing a clear-cut and successive treatment scheme from the emergency stage to the intensive care unit.

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PubMedDate not supplied

Ethyl carbamate metabolism: in vivo inhibitors and in vitro enzymatic systems.

The metabolism of ethyl carbamate and the localization of its metabolites have been shown to be almost completely inhibited by ethanol in the mouse [Waddell, Marlowe, Pierce: Food Chem. Toxicol.25, 527 (1987); Yamamoto, Pierce, Hurst, Chen, Waddell: Drug Metab. Dispos. 16, 355 (1988)]. The enzyme system catalyzing this metabolism which is inhibited by ethanol now has been further investigated in both in vivo and in vitro studies. There is a direct, highly significant relationship between the extent of metabolism of ethyl carbamate and covalent binding of metabolites to liver protein. Paraoxon, carbaryl, CCl4 ethanol, methimazole, 4-methylpyrazole, diethyl maleate, ethyl N-hydroxycarbamate, and t-butyl carbamate inhibit, to different extents, the metabolism of ethyl carbamate in vivo; SKF-525A, CoCl2, Cacyanamide, chloral hydrate, 2-oxo-4-thiazolidine carboxylic acid, allopurinol, and methyl carbamate do not. Porcine liver esterase, yeast aldehyde dehydrogenase and mouse liver catalase catalyzed the metabolism in vitro; dog or bovine catalase, acid phosphatase, alcohol dehydrogenase, or carbonic anhydrase did not under the conditions tested. Paraoxon, 4-methylpyrazole, carbaryl, and NaF significantly inhibited the hydrolytic activity of mouse liver homogenates toward p-nitrophenyl acetate; ethanol or ethyl carbamate did not. However, each of these, except 4-methylpyrazole, inhibited the metabolism of ethyl carbamate by mouse liver homogenate or porcine liver esterase to about the same extent. Ion exchange chromatography of mouse liver cytosol revealed that the fraction with ability to metabolize ethyl carbamate co-chromatographed almost exactly with the ability to hydrolyze p-nitrophenyl acetate. It is proposed that ethyl carbamate is metabolized in the mouse, at least partially, by esterases; however, metabolism by other enzyme systems cannot be excluded.

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PubMedDate not supplied

Inhibition of the metabolism of urethane by ethanol.

Ethanol has been shown to inhibit the localization of [ethyl-1-14C] urethane in the male mouse, but the effect of ethanol on the metabolism of urethane has not been clarified. Consequently, the concentration of unchanged urethane was determined in the blood of male mice up to 11 hr after oral administration of urethane with or without ethanol. A high and constant blood level of urethane persisted for 8 hr after the administration of an ethanolic solution of [ethyl-1-14C] urethane (125 mumol/kg, 10 muCi/20 g of mouse, 5 g of ethanol per kg, po); the blood level of ethanol was at or above 150 mg/dl during these 8 hr. In contrast, rapid clearance of radioactivity was observed in mice treated with [ethyl-1-14C]urethane dissolved in water. Coadministration of ethanol with urethane decreased the rate of 14CO2 expiration; furthermore, covalent binding with liver protein was delayed about 8 hr and was less than that in the group treated with urethane in water. The metabolism of urethane and production of 14CO2 from [carbonyl-14C]urethane by mouse liver homogenate in vitro were inhibited by the presence of ethanol (greater than 10 mM); these concentrations of ethanol in vitro are about the same as those that are inhibitory in vivo, but the extent of inhibition suggests that the liver is not the only site of metabolism of urethane. These results indicate that ethanol can inhibit the initial metabolism of urethane, prevent the formation of active metabolites, and allow urethane to persist in blood.

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PubMedDate not supplied

The biology and physiology of the ECL cell.

The enterochromaffin-like (ECL) cells, which are the predominant endocrine cell type in the acid-producing part of the vertebrate stomach, are characterized by numerous, electron-lucent vesicles and few electron-dense granules in the cytoplasm. The biological and physiological significance of the ECL cells remains poorly understood. They produce and store histamine and pancreastatin and are thought to produce an as yet unidentified peptide hormone. The most important clue to their function is their willingness to respond to changes in circulating gastrin. The present review presents current knowledge of the biology and physiology of the rat stomach ECL cells. Examination of serially sectioned ECL cells has revealed that the cytoplasmic vesicles almost invariably contain an electron-dense core, suggesting that perhaps the distinction between granules and vesicles is artificial. We propose a life cycle of the secretory organelles in the ECL cells with a progressive development from granules to vesicles. The results showed that the gastrin-evoked release of histamine and pancreastatin was accompanied by loss of vesicles, and that synthesis of histamine and pancreastatin was accelerated by sustained infusion of gastrin, a treatment that was associated with renewal of vesicles. The events described are instrumental in bringing about a change in the "steady state" or "equilibrium" of the ECL cells, from a non-stimulated, resting state to a gastrin-stimulated, active state. This change is attained within six to eight hr. The next "steady state" change is that from "normal-sized" but active ECL cells to "hypertrophic" ECL cells. The increase in cell size is complete after about one week. The gastrin-evoked increase in the ECL cell self-replication rate is maximal after about 10 days, after which time there is a gradual return back to pre-stimulation values. The ECL cell density increases fairly slowly and does not reach maximum (four-fold increase) until after 20 weeks hypergastrinemia. The activity of the histamine-forming enzyme, histidine decarboxylase, is elevated by gastrin and remains elevated for as long as the gastrin stimulus is maintained (the longest time studied was 20 weeks). The physiological significance of the ECL cells is probably related to their capacity to produce and store histamine and an as yet unidentified peptide hormone. The ECL cells are thought to be the source of histamine necessary for the gastrin-evoked acid response. In addition, preliminary evidence suggests that the ECL cells and the anticipated ECL cell hormone play a role in bone formation.

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